Analysis of the efficacy of hyperbaric oxygen therapy for disorders of consciousness: A retrospective cohort study

Abstract Objective To analyze the efficacy and associated factors affecting the prognosis in patients with disturbance of consciousness after hyperbaric oxygen (HBO) treatment. Methods A retrospective study was carried out on patients with disorders of consciousness (DOC) receiving HBO treatment from January to January 2022 in the Second Department of Rehabilitation Medicine of the Second Hospital of Hebei Medical University, China. Results HBO therapy improved the Glasgow Coma Scale (GCS) and Chinese Nanjing Persistent Vegetative State Scale (CNPVSS), as well as the clinical efficacy in patients with DOC. The comparison of GCS and CNPVSS scores in patients with DOC before and after HBO treatment was all statistically significant, with 325 patients (67.1%) showing effective results and 159 patients (32.9%) having unchanged outcomes. Univariate analysis indicated that there were statistically significant differences in age, HBO intervention time, HBO treatment times, pre‐treatment GCS score, and etiology and underlying diseases between the good and poor prognoses groups. Multivariate regression analysis showed that HBO intervention time ≤7 days, HBO treatment ＞ times, high GCS score before HBO treatment, and brain trauma were independent influencing factors in achieving a good prognosis for patients with DOC. Low pre‐treatment GCS scores were an independent risk factor for a poor prognosis in patients with brain trauma while being male, late HBO intervention time, fewer HBO treatment times, and low pre‐treatment GCS scores were independent risk factors for a poor prognosis in patients with DOC after a stroke. Being ≥50 years of age, late HBO intervention time, and low pre‐treatment GCS scores were independent risk factors for a poor prognosis in patients with DOC after hypoxic‐ischaemic encephalopathy. Conclusion HBO therapy can improve the GCS, CNPVSS scores and clinical efficacy in patients with DOC, and the timing of HBO intervention ≤7 days, times of HBO treatment, high pre‐treatment GCS score, and brain trauma were the independent influencing factors of good prognosis in patients with DOC.


INTRODUCTION
Disorders of consciousness (DOC) are a group of conditions that impair the level of awareness and responsiveness of patients after brain injury.
DOC can be caused by various etiologies, such as traumatic brain injury, stroke, and hypoxic-ischaemic encephalopathy (HIE).Patients with DOC pose a huge economic burden and mental stress to their families and society (Eapen et al., 2017).According to foreign research findings, there are 100,000-300,000 patients with DOC in the United States, and the average prevalence of DOC is about 0.2-6.1 per 100,000 in Europe (Song et al., 2020).In China, due to the large population base and the impact of traditional moral concepts, few people give up treatment.There are about -100,000 new cases of DOC in China every year, and the total cost of treatment is about 30-50 billion RMB per year (Zhao, 2020).Therefore, finding effective treatments for DOC is an urgent and important issue.
Hyperbaric oxygen (HBO) therapy is a method of treating diseases by inhaling pure oxygen in an environment above atmospheric pressure.HBO can increase the oxygen supply to the brain, reduce intracranial pressure, relieve brain oedema, enhance anti-inflammatory and anti-apoptotic effects, and promote neurogenesis and angiogenesis (Y.Zhang et al., 2023).In recent years, HBO has been widely used in patients with DOC after brain trauma (Chen et al., 2022), stroke (Y.Wang et al., 2015), and HIE (Chen et al., 2021), but its efficacy has not been fully established, and there is no widely accepted set of guidelines for its use in these indications.These practices are generally considered "off-label," and most practitioners treat the limited existing data for HBO in these indications with caution.Moreover, the existing studies on HBO for DOC have some limitations, such as small sample sizes, the lack of a control group, short follow-up periods, and inconsistent outcome measures (Hyldegaard & Hedetoft, 2020;Marcinkowska et al., 2022).Therefore, there is a need for more comprehensive and rigorous studies on the efficacy and safety of HBO for patients with DOC.
This study analyzed the efficacy and associated factors affecting the prognoses in patients with DOC after HBO treatment.To our knowledge, this is the largest and longest study on HBO for patients with DOC to date and provides valuable insights for clinical decision-making and future research.

Research object
A total of 545 patients with DOC treated by HBO in the Second Department of Rehabilitation Medicine, the Second Hospital of Hebei Medical University from January 2011 to January 2022 were retrospectively analyzed.The flowchart of patient recruitment and dropout is shown in Figure 1, which was created using the PRISMA flow diagram generator.A total of 484 subjects were finally included for clinical characteristics and therapeutic effect analysis.
A total of 437 subjects were screened, and the influencing factors were analyzed.This study was approved by the ethics committee of the Second Hospital of Hebei Medical University and conducted in accordance with the Declaration of Helsinki.All patients or their legal guardians signed an informed consent form before participating in the study.

Collecting data
Collecting basic information about all patients, gender, age, etiology, underlying disease, and patients' Glasgow Coma Scale (GCS) and Chinese Nanjing Persistent Vegetative State Scale (CNPVSS) on admission and discharge, as well as clinical efficacy were evaluated.The basic information and prognoses of patients were followed up by telephone after discharge.Patients were divided into groups based on the Glasgow Outcome Scale (GOS), with those achieving 1-3 points representing the poor prognosis group and 4-5 points representing the good prognosis group.

Inclusion criteria
The inclusion criteria for this study were as follows: (1) Patients with DOC with GCS scores below 8 points or conforming to a vegetative state (VS) and a minimally conscious state (MCS) diagnosis criteria (Kondziella et al., 2020); (2) patients with DOC arising from different causes, including brain trauma, stroke, and HIE; (3) the respiratory and circulatory system indexes and vital signs of the patient were stable; (4) course of disease was within 3 months; (5) all patients had first onset; (6) the total number of HBO treatments should not be fewer than 10.

Exclusion criteria
The exclusion criteria for this study were as follows:

Instruments
The instruments used in this study were as follows: 1.

Research grouping
Patients were divided into poor and good prognoses groups according to the GOS scores at follow-up.

Treatment methods
All patients received routine monitoring of blood pressure, an electrocardiogram, and oxygen saturation, and they were given symptomatic treatment with drugs and underwent surgery according to their condition.Targeted rehabilitation treatment was given according to the specific dysfunction of the patients, including transcranial direct current stimulation, myoelectric biofeedback, neuroelectric biomimetic stimulation and the passive training of lower limb intelligence, and swallowing electrical stimulation.Based on these results, all of the patients received HBO treatment.The medical HBO three-chamber seven-door air-pressurized chamber was used to deliver treatment at pressure ranges of 1.4-2.2atmospheres absolute (ATA) (1.4-1.6 ATA for infants, 1.6-1.8ATA for patients in a serious condition, the elderly, and the infirm, as well as for those with complications such as otorrhea and rhinorrhoea; 1.8-2.2ATA was applied for stable patients).
The pressure was applied for 25 min until reaching the desired level.
Then, pure oxygen was inhaled for 30 min, followed by a 10-min air break and another 30-min session of pure oxygen inhalation.Thereafter, the pressure was reduced over 25 min until returning to normal, once a day, 7 days per week, 30 times for each course of treatment, with a resting period of 5-7 days after each course of treatment.

Evaluation methods
We used the following methods to evaluate the levels of consciousness, outcomes, and clinical efficacy of the treatment among patients:

The GCS scoring scale
This is a widely used scale for measuring the level of consciousness in patients with brain injuries and comprises three components: eyeopening response (E), verbal response (V), and motor response (M) (Teasdale & Jennett, 1974).The total score ranges from 3 (deep coma) to 15 (normal consciousness).The higher the score, the better the state of consciousness of the patient; the lower the score, the more serious the DOC (Yang et al., 2021).

GOS outcome scale
This is a widely used scale to assess the outcome of brain injury, ranging from 1 (death) to 5 (slight defect) (Jennett & Bond, 1975;Sun et al., 2021;Yuan et al., 2022).A higher score indicated a less severe craniocerebral injury.We divided the patients into poor and good prognoses groups according to the GOS scores at follow-up, with 1-3 points reflecting a poor result and 4-5 points indicating a good outcome.

Evaluation of clinical efficacy
We used the following criteria to evaluate the clinical efficacy of HBO treatment based on the changes in GCS and CNPVSS scores after treatment (Fan et al., 2015;Tian et al., 2012): 1. Essentially cured: The patient was sober, with a GCS score of 15 points or an overall CNPVSS score increase of more than 8 points.
2. Significant effect: Symptoms and signs were significantly improved, GCS score >12 points or CNPVSS score increased by 5-8 points.
4. Invalid: Symptoms and signs did not improve, GCS score, CNPVSS score did not increase or decrease.
5. Total effective rate = (number of basically cured cases + number of significantly effective cases + number of effective cases)/total cases × 100%.

Statistical methods
The experimental results were analyzed and processed by the SPSS 26.0 statistical software.In the measurement data, normally distributed data were expressed as mean ± standard deviation (x ± s), while skewed distribution data were expressed as median and quartile spacing.A paired t-test or nonparametric test was used to compare the changes in GCS scores before and after treatment.A χ 2 test or rank-sum test was used for counting data.Univariate analysis was performed on the relevant factors affecting the curative effect of HBO.
Then, multivariate logistic regression analysis was performed on the significant factors; α = .05was selected as the test level, and p < .05 was considered statistically significant.

GCS score
The GCS score of the patients before HBO treatment was 3-12 points, with a median and quartile of 6 (4, 8) points.After HBO treatment, the GCS score was 3-15 points, with a median and quartile of 10 (7, 13.75) points.A paired rank-sum test was performed for GCS scores before and after HBO treatment, and the difference was statistically significant (z = −19.482,p < .01).

CNPVSS score
The CNPVSS scores of the patients before HBO treatment were 0-8 points, and median and quartile scores were 2 (1, 2) points.After HBO treatment, the CNPVSS scores were 0-17 points, and median and quartile scores were 7 (3, 12) points.A paired rank-sum test was performed for the CNPVSS scores before and after HBO treatment, and the difference was statistically significant (z = −17.651,p < .01).

Evaluation of clinical efficacy
We classified the clinical efficacy into four categories based on the changes in GCS and CNPVSS scores after HBO treatment: essentially cured, significant effect, valid, and invalid.

Single factor analysis
There were statistically significant differences between the good prognosis and the poor prognoses groups in age, HBO intervention time, HBO treatment frequency, GCS score before treatment, etiology, underlying diseases (hypertension, diabetes, coronary heart disease, and cerebrovascular disease), combined rehabilitation therapy, and HBO treatment pressure (p < .05)(Table 1).

Multi-factor analysis
Logistic multivariate regression analysis showed that late HBO intervention, fewer HBO treatments, a low GCS score before HBO treatment, and DOC caused by HIE were risk factors for a poor prognosis in patients with DOC (p < .05)(Table 2).

Univariate analysis
There were statistically significant differences in age, GCS score before HBO treatment, whether combined rehabilitation treatment was provided, and HBO treatment stress between the good prognosis and poor prognosis groups after traumatic brain injury (p < .05)(Table 3).

Multiple-factor analysis
Logistic regression analysis indicated that a low GCS score before HBO treatment was a risk factor for a poor prognosis among patients with DOC after a traumatic brain injury (p < .05)(Table 4).

Univariate analysis
There were statistically significant differences in gender, HBO intervention time, HBO treatment times, and pre-treatment GCS scores between the good and poor prognoses groups after stroke (p < .05)(Table 5).

Multi-factor analysis
The logistic multivariate regression analysis demonstrated that being male, a late HBO intervention time, fewer HBO treatments, and low pre-treatment GCS scores were risk factors for a poor prognosis among patients with DOC after stroke (p < .05)(Table 6).

Prognostic factor analysis for patients with DOC after HIE Single-factor analysis
There were statistically significant differences in age, HBO intervention time, and GCS scores before HBO treatment between the good and bad prognoses groups of patients with DOC combined with HIE (p < .05)(Table 7).

Multivariate analysis
Logistic regression analysis showed that an age ≥50 years, HBO intervention timing, and low pre-treatment GCS scores were risk factors for a poor prognosis among patients with DOC, a previous diagnosis of HIE (p < .05)(Table 8).

Efficacy analysis of HBO on patients with DOC
HBO therapy is used to treat diseases by inhaling pure oxygen in an environment above atmospheric pressure.In recent years, studies both at home and abroad have shown that HBO has a good therapeutic effect on DOC, which can improve the GCS, CNPVSS, and GOS scores of patients with DOC with different etiologies, improve their prognosis, and shorten coma times (Ahmadi & Khalatbary, 2021;Joshua et al., 2022;Y. S. Liu, Liu, et al., 2022;M. Liu, Li, et al., 2022;S. Y. Zhang et al., 2017).In this study, we analyzed patients with DOC who had been treated over the past 10 years.The GCS and CNPVSS scores of patients with DOC caused by brain trauma, stroke, and HIE were increased after HBO treatment, and the total effective rate was 67.1%.HBO therapy can improve brain metabolism, inhibit neuro-inflammatory reactions, and recover nerve function, thus promoting patients to regain consciousness, shortening coma time, helping patients to recover cognitive and motor functions, and improving their daily activity abilities, thereby significantly improving the clinical efficacy and prognosis of patients (Hadanny et al., 2020;Hu et al., 2016 Abbreviations: CI, confidence interval; GCS, Glasgow Coma Scale; HBO, hyperbaric oxygen; OR, odds ratio.

Age and DOC prognosis
With increased ageing, the cerebral cortex degenerates, and the metabolic and regenerative abilities of cells in various tissue types and organs decrease to different degrees, while levels of neurotransmitters, such as acetylcholine and GABA is an important neurotransmitter in the central nervous system and has a regulatory role in a variety of body functions, also change the body (Gong et al., 2017;Guo et al., 2017).It has been noted that the total clinical response rate in patients aged <50 years is higher than in patients aged ≥50 years following HBO treatment (Pan, 2015), and that the recovery rate in patients with advanced PVS after HBO treatment is lower in patients with DOC (P.Wu et al., 2017).The univariate analysis of this study showed that the good prognosis rate of patients aged <50 years (76.0%) was higher than that of patients aged ≥50 years (56.3%), and the difference was statistically significant.However, there was no significant association between age and prognosis in patients with DOC, which is inconsistent with previous findings, possibly because the prognosis of patients is closely related to different diseases and their severity.Additionally, no direct relationship was observed between age and the severity of DOC in patients.

Timing of HBO intervention and DOC prognosis
In the early stages of brain injury, HBO can reduce neuroinflammatory responses, improve neurological function damage, and promote the recovery of consciousness in patients (Geng et al., 2016;Y. Huang et al., 2022); in the late stages of brain injury, HBO can reduce neuroinflammatory responses by increasing arterial partial pressure of oxygen and oxygen content, improving brain tissue cell metabolism, and promoting nerve cell remodeling (Ortega et al., 2021).Studies have shown that the clinical efficacy rate of patients with DOC who started treatment 8-12 days after injury is higher than that of patients who started treatment 16-30 days after injury (Z.Huang et al., 2016).Early HBO intervention can improve the GCS and GOS scores of patients and their prognosis (Ortega et al., 2021;D. Wang et al., 2018).The multivariate analysis showed that, compared with patients whose time of HBO intervention was fewer than 7 days, the patients for whom this was 8-14 days, 15-30 days, and more than 30 days had a 6.886, 14.011, and 29.268fold higher rate of poor prognosis, respectively, demonstrating that an HBO intervention time ≤7 days reflected a significant improvement in patient prognosis; these results are similar to those presented in previous studies.Accordingly, when the vital signs of patients with DOC are stable, HBO therapy should be given within 7 days after the onset of the disease, as doing so can help to improve the patient's prognosis.
TA B L E 3 Univariate analysis of disorders of consciousness (DOC) patients after traumatic brain injury.

Times of HBO treatment and prognosis of DOC
Multiple studies have underscored the frequency of HBO therapy as an independent factor influencing the effectiveness of treatment in patients with DOC caused by cerebral infarction (L.Liu et al., 2020), brain trauma (C.Huang & Liu, 2015;R. Wu, 2016), and HIE (Ye, 2020).Chen et al. (2021) showed that HBO therapy could improve the state of consciousness of patients with severe traumatic brain injury and suggested that patients with VS or MCS receive HBO therapy for more than 20 consecutive days.Our analysis of patients with DOC over the past decade found that the adverse prognosis rate of patients with TA B L E 4 Multivariate analysis of disorders of consciousness (DOC) patients after traumatic brain injury.

GCS score and DOC prognosis before HBO treatment
Multiple studies have shown that the lower the GCS score, the more severely damaged the brain tissue of the patient will be and, accordingly, the worse their prognosis (Zou & Luo, 2022).Additionally, a lower GCS score is a risk factor for poor prognosis in patients with DOC (Bao et al., 2021;Galea et al., 2017;Zhou, 2020).Our multivariate analysis also found that each one-point reduction in the GCS score was associated with a 0.621-fold increased risk of poor outcome.The lower the GCS score and the deeper the coma state of the patient at admission, the higher the risk of irreversible nerve cell damage and the worse the indicated prognosis.

DOC etiology and prognosis
DOC can be caused by brain trauma, stroke, and HIE.The results of this study showed that, compared with HIE, patients with DOC caused by brain trauma had a better prognosis rate, and the difference was statistically significant, which is consistent with the results in other literature (Y.Liu et al., 2022).The outcomes of the present study found no statistically significant difference concerning the outcomes of patients with DOC after brain injury and stroke, however, which may be due to this having been a retrospective study; inevitably, there were confounding factors in data collection and follow-up.The results of this study require further examination using strict and normative prospective research.

Analysis of prognostic factors in patients with DOC after traumatic brain injury
Through the analysis of patients with DOC arising from different causes, this study found that 80% of 220 patients with DOC caused by traumatic brain injury had a good prognosis.Multivariate analysis found that a low GCS score before HBO treatment was an independent risk factor for the poor prognosis of patients with DOC after traumatic brain injury.However, age, whether combined rehabilitation therapy was applied or not, and HBO treatment pressure settings were not identified as independent risk factors for a poor prognosis in patients with DOC after traumatic brain injury.

Analysis of prognostic factors in patients with DOC after stroke
In this study, 116 patients with DOC caused by stroke were analyzed.
The results indicated that being male was an independent risk factor for receiving a poor prognosis among patients with DOC after stroke; the risk of a poor prognosis in men was 0.345 times higher than for women, which is inconsistent with previous research results (Xiao, 2019;Xun et al., 2021).The reason for the higher risk of an adverse prognosis in men in this study may be because the research was retrospective in nature with unbalanced gender grouping.Male participants accounted for a significant proportion of patients in this study.It is hoped that prospective studies with balanced grouping could be carried out in the future to further analyze the relationship between gender and the prognosis of patients with DOC after stroke.The multifactor analysis in this study also found that a late HBO intervention time, fewer HBO treatments, and low GCS scores before HBO treatment were independent risk factors for the poor prognosis of patients with DOC after stroke, which was consistent with previous studies (Alonso et al., 2015).
TA B L E 7 univariate analysis of disorders of consciousness (DOC) patients after hypoxic-ischemic encephalopathy.

General information
Poor (1) Patients with unstable vital signs; (2) patients with severe cardiac, liver, and renal dysfunction, hematological diseases and immune dysfunction; (3) patients with HBO contraindications, such as untreated pneumothorax, concurrent use of doxorubicin or disulfiram, chronic obstructive pulmonary disease or asthma with air-trapping risk, recent ear surgery or injury, or claustrophobia; (4) patients who died during The flowchart of patient recruitment and dropout.DOC, disorders of consciousness; HBO, hyperbaric oxygen.hospitalization due to other diseases; (5) patients with incomplete medical records.
Comparison of general data of disorders of consciousness (DOC) patients with good prognosis and poor prognosis.In the HBO treatment pressure group, 2.0ATA refers to the highest pressure of 2.0ATA after the condition is stabilized, 2.2ATA refers to the highest pressure of 2.2ATA after the condition is stabilized.
frequency of HBO therapy, GCS score before HBO therapy, etiology, underlying diseases (hypertension, diabetes, coronary heart disease, and cerebrovascular disease), combined rehabilitation therapy, and the specific pressure used during HBO therapy were all influencing factorsTA B L E 1Abbreviations: ATA, atmospheres absolute; GCS, Glasgow Coma Scale; HBO, hyperbaric oxygen.Note: ① Logistic multivariate regression analysis.

Poor prognosis group (n = 44) Good prognosis group (n = 176) χ 2 /z value p value
Univariate analysis of disorders of consciousness (DOC) patients after stroke.Multivariate analysis of disorders of consciousness (DOC) patients after stroke.
Multivariate analysis of disorders of consciousness (DOC) patients after hypoxic ischemic encephalopathy.